rs139633388
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2
The NM_000096.4(CP):āc.2684G>Cā(p.Gly895Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,726 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0016 ( 0 hom., cov: 32)
Exomes š: 0.0019 ( 3 hom. )
Consequence
CP
NM_000096.4 missense
NM_000096.4 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
CP (HGNC:2295): (ceruloplasmin) The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP3
?
Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.14648741).
BS2
?
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CP | NM_000096.4 | c.2684G>C | p.Gly895Ala | missense_variant | 16/19 | ENST00000264613.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CP | ENST00000264613.11 | c.2684G>C | p.Gly895Ala | missense_variant | 16/19 | 1 | NM_000096.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00156 AC: 237AN: 151782Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00152 AC: 380AN: 250058Hom.: 0 AF XY: 0.00160 AC XY: 217AN XY: 135310
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GnomAD4 exome AF: 0.00185 AC: 2703AN: 1459826Hom.: 3 Cov.: 31 AF XY: 0.00186 AC XY: 1354AN XY: 726376
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GnomAD4 genome ? AF: 0.00156 AC: 237AN: 151900Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110AN XY: 74260
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:11Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Deficiency of ferroxidase Pathogenic:1Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Apr 18, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jan 27, 2022 | - - |
not provided Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 09, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 13, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CP: PP3, BP2 - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27753142, 28968711, 18293024, 16629161, 34426522, 31785789, 33774058, 34274368, 32235485, 36233161) - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 04, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 13, 2023 | Variant summary: CP c.2684G>C (p.Gly895Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250058 control chromosomes (gnomAD), predominantly at a frequency of 0.0024 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Ten ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance, one as likely pathogenic, and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Hypoceruloplasminemia Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | DASA | Feb 14, 2022 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (DOI:10.1016/j.mgene.2021.100905) - PS3_supporting. The c.2684G>C;p.(Gly895Ala) missense variant has been observed in affected individual(s) (PMID: 32235485; 27753142; 20301666; https://doi.org/10.1016/j.mgene.2021.100905) - PS4_supporting. The variant is present at low allele frequencies population databases (rs139633388 - gnomAD 0.01561%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly895Ala) was detected in trans with a pathogenic variant (PMID: 32235485; 27753142; https://doi.org/10.1016/j.mgene.2021.100905) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32235485) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Vest4
0.98
MVP
MPC
0.50
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at